During the aging process, rates of protein degradation decrease, and this effect can contribute to the accumulation of cytotoxic proteins. This observation suggests that in Alzheimer's disease and other tauopathies the presence of tangles (a pathological hallmark of these diseases) may be due to the impaired clearance of abnormal tau by cellular protein quality control systems. While it is believed that the accumulation of tau in these diseases is the product of posttranslational modifications, little information is specifically available about the degradation processes of tau. In eukaryotes, the major quality control systems that degrade proteins are the autophagy pathway and the ubiquitin-proteasome system (UPS). Autophagy is a highly regulated process that involves the bulk degradation of long-lived cytoplasmic macromolecules and organelle structures in the eukaryotic systems through the lysosomal/vacuolar system, whereas the UPS selectively degrades a majority of short-lived cellular proteins. While existing publications on tau turnover have suggested that this protein is eliminated through the UPS, we have identified autophagy-mediated degradation as a major route for disposal of tau protein. Furthermore, we have found that the upregulation of lysosomal enzymes by treatment with a class of well-tolerated, blood-brain-barrier penetrant compounds results in a highly significant reduction of mutant tau protein. Taken together, this data shows that compounds that directly target lysosomal degradation pathways are potentially important in the treatment of tauopathies. This proposal will (1) characterize whether perturbations of the lysosomal and autophagy pathways can affect the trafficking and degradation of both normal and aggregation-prone forms of tau; (2) determine if blockade of the autophagy pathway impairs recovery of spatial memory in inducible tau transgenic mice, and (3) determine if lysosomal activation protects against neurodegeneration in tau transgenic mice. This R21 grant proposal represents a novel direction in the effort to unravel the mechanisms governing the degradation of tau protein and may lead to new tools for the treatment of tauopathies and other neurodegenerative diseases. [unreadable] [unreadable]